ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1994T>C (p.Ile665Thr) (rs1064793789)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772636 SCV000905841 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000481061 SCV000567039 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.1994T>C at the cDNA level, p.Ile665Thr (I665T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile665Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ile665Thr occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Ile665Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000627944 SCV000748829 uncertain significance Ataxia-telangiectasia syndrome 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 665 of the ATM protein (p.Ile665Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 419317). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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